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- Vogel, Jacob W., et al.
(författare)
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Four distinct trajectories of tau deposition identified in Alzheimer’s disease
- 2021
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:5, s. 871-881
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 4. |
- Budd Haeberlein, Samantha, et al.
(författare)
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Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease
- 2022
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Ingår i: Journal of Prevention of Alzheimer's Disease. - : SERDI. - 2274-5807. ; 9:2, s. 197-210
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alzheimer’s disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. Objectives: We evaluated the efficacy and safety of aducanumab in early Alzheimer’s disease. Design: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer’s disease. Setting: These studies involved 348 sites in 20 countries. Participants: Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50–85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, of which 1812 (55.2%) completed the study. Intervention: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (10 mg/kg target dose), or placebo via IV infusion once every 4 weeks over 76 weeks. Measurements: The primary outcome measure was change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; and biomarker endpoints. Results: EMERGE and ENGAGE were halted based on futility analysis of data pooled from the first approximately 50% of enrolled patients; subsequent efficacy analyses included data from a larger data set collected up to futility declaration and followed prespecified statistical analyses. The primary endpoint was met in EMERGE (difference of -0.39 for high-dose aducanumab vs placebo [95% CI, -0.69 to -0.09; P=.012; 22% decrease]) but not in ENGAGE (difference of 0.03, [95% CI, -0.26 to 0.33; P=.833; 2% increase]). Results of biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer's disease pathophysiology. The most common adverse event was amyloid-related imaging abnormalities-edema. Conclusions: Data from EMERGE demonstrated a statistically significant change across all four primary and secondary clinical endpoints. ENGAGE did not meet its primary or secondary endpoints. A dose-and time-dependent reduction in pathophysiological markers of Alzheimer’s disease was observed in both trials.
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| 5. |
- Lind, C. M., et al.
(författare)
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Effectiveness and usability of real-time vibrotactile feedback training to reduce postural exposure in real manual sorting work
- 2023
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Ingår i: Ergonomics. - : Informa UK Limited. - 0014-0139 .- 1366-5847. ; 66:2, s. 198-216
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Tidskriftsartikel (refereegranskat)abstract
- Vibrotactile feedback training may be used as a complementary strategy to reduce time in demanding postures in manual handling. This study evaluated the short- and medium-term effects of concurrent posture-correction vibrotactile feedback training on trunk inclination exposure in real manual sorting work. Fifteen warehouse workers completed the training and the follow-up sessions. Trunk inclination angles were recorded using the ambulatory Smart Workwear System. Questionnaires were used for assessing system usability, perceived physical exertion, and work ability. The results showed reduced time in trunk inclination >30°, >45°, and >60°, and reductions in the 90th, 95th, and 99th percentile trunk inclination angles, when receiving feedback and immediately after feedback withdrawal. No significant reduction was retained after one and three weeks. The wearer's comfort was scored high, and the feedback did not increase the perceived cognitive demands. No significant effects attributed to changed trunk inclination exposure were observed for perceived physical exertion or work ability. The training program has the potential of contributing to reduced trunk inclination exposure in the short term. Future studies are needed to evaluate if improvements in the feedback training can transfer the short-term results to retained median- and long-term effects. Practitioner summary: A two-day training program with concurrent posture-correction vibrotactile feedback can contribute to reduced exposure of trunk inclination in real manual sorting work in the short term. More research is needed on how to design the feedback training programs in order to be effective in the long term.
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| 6. |
- Ek, M., et al.
(författare)
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Probing Catalyst Surfaces at the Atomic-scale
- 2023
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Ingår i: Microscopy and microanalysis : the official journal of Microscopy Society of America, Microbeam Analysis Society, Microscopical Society of Canada. - 1435-8115. ; 29:1, s. 1291-1291
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Tidskriftsartikel (refereegranskat)
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| 8. |
- Mallinckrodt, C., et al.
(författare)
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Investigating Partially Discordant Results in Phase 3 Studies of Aducanumab
- 2023
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Ingår i: Journal of Prevention of Alzheimer's Disease. - : SERDI. - 2274-5807. ; 10, s. 171-177
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Efficacy and safety results from the EMERGE (NCT02484547) and ENGAGE (NCT02477800) phase 3 studies of aducanumab in early Alzheimer’s disease (AD) have been published. In EMERGE, but not in ENGAGE, high-dose aducanumab demonstrated significant treatment effects across primary and secondary endpoints. Low-dose aducanumab results were consistent across studies with non-significant differences versus placebo that were intermediate to the highdose arm in EMERGE. The present investigation examined data from EMERGE and ENGAGE through post-hoc analyses to determine factors that contributed to discordant results between the high-dose arms of the two studies. Design: EMERGE and ENGAGE were 2 phase 3, randomized, double-blind, placebo-controlled, parallel-group studies. Setting: EMERGE and ENGAGE were 2 global multicenter studies involving 348 sites in 20 countries. Participants: Participants in EMERGE and ENGAGE were aged 50 to 85 years and had mild cognitive impairment or mild AD dementia with confirmed amyloid pathology. The randomized and dosed population (all randomized patients who received at least one dose of study treatment) included 1638 patients in EMERGE and 1647 in ENGAGE. Intervention: In EMERGE and ENGAGE, participants were randomized to receive low- or high-dose aducanumab or placebo (1:1:1) once every 4 weeks. Measurements: In this paper, 4 areas were investigated through post-hoc analyses to understand the discordance in the high-dose arms of the EMERGE and ENGAGE studies: baseline characteristics, amyloid-related imaging abnormalities, non-normality of the data, and dosing/exposure to aducanumab. Results: Post-hoc analyses showed that outcomes in the ENGAGE high-dose group were affected by an imbalance in a small number of patients with extremely rapid progression and by lower exposure to the target dose of 10 mg/kg. These factors were confounded and present in early enrolled patients but were not present in later-enrolled patients who were randomized to the target dosing regimen of 10 mg/kg after titration. Neither baseline characteristics nor amyloid-related imaging abnormalities contributed to the difference in results between the high-dose arms. Conclusions: Results were consistent across studies in later enrolled patients in which the incidence of rapidly progressing patients was balanced across treatment arms.
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